The main goal of our work is to understand the development and function of the mammalian olfactory system. Our focus has been on the role of sensory induced plasticity in the assembly and maintenance of neural circuits in the olfactory bulb (OB). The OB receives direct input from regenerating olfactory sensory neurons (OSNs) in the nasal cavity and then relays the information to the olfactory cortex. The OB also receives central extensive top-down projections from various cortical regions, making the OB a central processing hub for olfactory information. OB circuitry is highly organized, with distinct anatomical and functional maps, which are maintained in the presence of ongoing regeneration and are constantly refined by activity-dependent plasticity. Our recent work has found that regenerating OSNs exhibit extensive synaptic reorganization that continues even after they mature and that newly generated neurons from the subventricular zone (SVZ) are not only required to build appropriate OB circuits but that their continuous turnover is necessary to maintain circuit organization. By manipulating odorant-induced activity we found that many aspects of the OB circuitry can be regulated by sensory input including the flow of neuroblasts from the SVZ. What remains unknown are the mechanisms that underlie the maintenance of OB circuits in the face of continuous regeneration or that mediate their activity-dependent plasticity. Thus, our current efforts focus on three aims: 1) We seek to define the mechanisms that regulate OSN development and connectivity. We previously showed that the developmental stage of OSNs is an important factor in regulating odorant receptor (OR) expression and highlighted an important transition phase between immature and mature OSNs. This phase corresponds to the period of OR selection and initial OSN synapse formation in the OB but little is known about the OSN in this state. Thus, we will use a multifactied molecular a functional approach to understand the basis if this transitional phase and how it relates to OB connectivity; 2) We will determine the factors that mediate intrabulbar plasticity. We previously showed that the accuracy of intrabulbar projections (IBP) is dependent upon a combination of sensory induced activity and regeneration but the precise interply bwtween these dynamic processes remains unclear. Thus, we will utilize a combinaiton of pharmacogenetic techniques an multeielectrod recordings to identify the specific cell types and molecules that are responsible for the IBP plasticity in response to odor stimulation; and 3) We will delineate the role of specific cortical inputs to OB function and IBP plasticity. Since the OB receives top-down input from many brain regions, including olfactory cortical areas and other neuromodulatory centers that can regulate OB activity, we will use transgenic mice to model olfactory behaviors that assciated with OB plasticity and test the involvement of the various top-down inputs. Together, these experiments will provide a better understanding of basic OB function and its plasticity.